We propose a systematic proteomic analysis of the human innate immune response to DNA infection coupled with a functional analysis of genes in the network. We focus on the signaling pathways involved in transcription of type I interferon. This project provides a glimpse into the global architecture of antiviral signaling and serves as a resource for further mechanistic analysis of the pathway. PUBLIC HEALTH RELEVANCE:: The molecular mechanisms involved in regulating innate immune responses to DNA viruses are incompletely understood. We propose a systematic proteomic approach to discover the molecular signaling pathways controlling responses to DNA and DNA viruses.